Dabrafenib plus trametinib in patients with -mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial

The Lancet Oncology, July 2017, Volume 18, Issue 7, Pages 863-873

Abstract

Summary

Background

Dabrafenib plus trametinib improves clinical outcomes in BRAF V600 -mutant metastatic melanoma without brain metastases; however, the activity of dabrafenib plus trametinib has not been studied in active melanoma brain metastases. Here, we report results from the phase 2 COMBI-MB trial. Our aim was to build on the current body of evidence of targeted therapy in melanoma brain metastases through an evaluation of dabrafenib plus trametinib in patients with BRAF V600 -mutant melanoma brain metastases.

Methods

This ongoing, multicentre, multicohort, open-label, phase 2 study evaluated oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in four patient cohorts with melanoma brain metastases enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAF V600E -positive, asymptomatic melanoma brain metastases, with no previous local brain therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (B) BRAF V600E -positive, asymptomatic melanoma brain metastases, with previous local brain therapy, and an ECOG performance status of 0 or 1; (C) BRAF V600D/K/R -positive, asymptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0 or 1; and (D) BRAF V600D/E/K/R -positive, symptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0, 1, or 2. The primary endpoint was investigator-assessed intracranial response in cohort A in the all-treated-patients population. Secondary endpoints included intracranial response in cohorts B, C, and D. This study is registered with ClinicalTrials.gov , number NCT02039947 .

Findings

Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. At the data cutoff (Nov 28, 2016) after a median follow-up of 8·5 months (IQR 5·5–14·0), 44 (58%; 95% CI 46–69) of 76 patients in cohort A achieved an intracranial response. Intracranial response by investigator assessment was also achieved in nine (56%; 95% CI 30–80) of 16 patients in cohort B, seven (44%; 20–70) of 16 patients in cohort C, and ten (59%; 33–82) of 17 patients in cohort D. The most common serious adverse events related to study treatment were pyrexia for dabrafenib (eight [6%] of 125 patients) and decreased ejection fraction (five [4%]) for trametinib. The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (four [3%] of 125) and headache (three [2%]).

Interpretation

Dabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with BRAF V600 -mutant melanoma without brain metastases, but the median duration of response was relatively short. These results provide evidence of clinical benefit with dabrafenib plus trametinib and support the need for additional research to further improve outcomes in patients with melanoma brain metastases.

Funding

Novartis.

Introduction

Among common cancers, metastatic melanoma has the highest risk of spreading to the CNS. 1 2 The development of brain metastases in patients with melanoma has been observed at an incidence of up to 43% in clinical studies and 75% in autopsy studies. 2 3 Historically, brain metastases in patients with metastatic melanoma have been associated with poor overall survival (median 4–5 months), and the poorest outcomes are observed in those presenting with neurological symptoms and leptomeningeal involvement. 4 5 Various targeted therapies (ie, BRAF and MEK inhibitors) and checkpoint inhibitor immunotherapies (ie, anti-CTLA-4 and anti-PD-1 antibodies, alone or combined) available for the treatment of BRAF V600 -mutant melanoma have significantly improved clinical outcomes in patients with metastatic disease. 6 7 8 9 10 However, patients with active brain metastases have typically been excluded from large trials to date, and treatments specifically indicated for the treatment of melanoma brain metastases remain an unmet need.

In the phase 2 BREAK-MB trial, 11 dabrafenib monotherapy showed clinical activity and had a manageable safety profile in patients with BRAF V600E -mutant melanoma brain metastases (n=139), including patients with or without previous local treatment for brain metastases. In patients with BRAF V600E -mutant melanoma without previous local treatment (n=74), 39% of patients achieved an overall intracranial response and 38% achieved an overall response by investigator assessment. In patients with BRAF V600E -mutant melanoma with previous local treatment (n=65), 31% of patients achieved both an investigator-assessed overall intracranial response and an overall response. In both BRAF V600E groups, 6-month overall survival was 61%. Fewer patients with BRAF V600K -mutant disease included in the study (n=33) had a response, regardless of whether they had received previous local treatment (overall intracranial response was achieved in 22% of patients who did not have previous treatment and 7% of patients who had previous treatment). Small cohorts of molecularly unselected patients with asymptomatic brain metastases have also been shown to have a response to ipilimumab (16% of 51 patients achieved a brain metastasis response) and pembrolizumab (22% of 18 patients achieved a brain metastasis response) in prospective clinical trials. 12 13

Evidence before this study

We searched PubMed for clinical studies published up to March 7, 2017, with the search terms “BRAF”, “melanoma”, and “brain metastases”, and identified 144 articles, of which four were primary analyses of phase 1 or 2 clinical trials of BRAF inhibitor regimens in patients with BRAF V600 -mutant melanoma brain metastases. BRAF inhibitor monotherapy has previously been shown to have clinical activity and tolerability in patients with BRAF -mutant melanoma who developed metastases in the brain. Although the BRAF and MEK inhibitor combination therapy has been shown to be superior to BRAF inhibitor monotherapy in patients with BRAF V600 -mutant metastatic melanoma without brain metastases, the clinical effect of this regimen on melanoma brain metastases has not been characterised.

Added value of this study

Intracranial outcomes showed that dabrafenib plus trametinib was active in patients with BRAF V600 -mutant melanoma brain metastases and the primary study endpoint was met; however, responses did not last as long as those previously observed for the combination in patients with melanoma without brain metastases. No unexpected safety issues were observed with dabrafenib plus trametinib in this setting. Our findings represent the first report, to our knowledge, of a phase 2 trial evaluating BRAF and MEK inhibitor combination therapy in patients with melanoma brain metastases and provide evidence that clinical benefit and tolerability are achievable with dabrafenib plus trametinib in a subset of patients with BRAF V600 -mutant melanoma that has metastasised to the brain.

Implications of all the available evidence

Continued follow-up in this study is necessary to determine the full effect of dabrafenib plus trametinib on overall survival in this setting; however, these preliminary results support the use of this targeted therapy combination as a treatment option for these patients, in whom effective treatments remain a critical unmet medical need.

Research in context

The combination of dabrafenib and trametinib has been shown to improve progression-free survival and overall survival compared with that seen for BRAF inhibitor monotherapy, with a manageable safety profile in phase 2 and phase 3 trials of patients with BRAF V600E/K -mutant stage IIIC unresectable or stage IV metastatic melanoma without brain metastases. 6 7 14 15 16 17 18 19 However, this combination targeted therapy has not been previously evaluated prospectively in patients with BRAF V600 -mutant melanoma brain metastases.

Here, we report the primary analysis of the phase 2 COMBI-MB trial evaluating dabrafenib plus trametinib in patients with active BRAF V600 -mutant melanoma brain metastases.

Methods

Study design and patients

This multicentre, open-label, multicohort, phase 2 trial evaluated the activity and safety of dabrafenib plus trametinib in four patient cohorts enrolled from 32 hospitals and institutions in Europe, North America, and Australia ( appendix p 9 ): cohort A included patients with BRAF V600E -mutant, asymptomatic melanoma brain metastases, without previous local brain-directed therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; cohort B included patients with BRAF V600E -mutant, asymptomatic melanoma brain metastases, with previous local therapy, and an ECOG performance status of 0 or 1; cohort C included patients with BRAF V600D/K/R -mutant, asymptomatic melanoma brain metastases, with or without previous local therapy, and an ECOG performance status of 0 or 1; and cohort D included patients with BRAF V600D/E/K/R -mutant, symptomatic melanoma brain metastases, with or without previous local therapy, and an ECOG performance status of 0, 1, or 2 ( appendix p 2 ).

Patients aged 18 years or older with histologically confirmed stage IV metastatic BRAF V600D/E/K/R -mutant cutaneous melanoma, diagnosed using the THxID BRAF assay (investigational use only; bioMerieux, Marcy-l'Étoile, France) at a central reference laboratory, were eligible for enrolment. Target lesions could be 0·5–4·0 cm in diameter; we excluded patients with the presence of any leptomeningeal disease or parenchymal brain metastasis measuring more than 4·0 cm in diameter. Patients with any RAS -mutant positive malignancy, history of malignancy other than the disease under study within 3 years (except completely resected non-melanoma skin cancer or patients with indolent malignancies), history of hepatitis B virus or hepatitis C virus without laboratory evidence of clearance, and any other serious or unstable pre-existing medical conditions or psychiatric disorders that could interfere with patient safety, consent, or compliance to study procedures were not eligible. Adequate organ function was also required for eligibility. Patients could have received up to two previous systemic therapies for metastatic melanoma, except for BRAF or MEK inhibitors. Previous temozolomide therapy for brain metastases and adjuvant interferon were permitted and did not count towards the maximum of two previous systemic treatments. Previous systemic anticancer treatment in the 3 weeks preceding the first dose of the combination, and chemotherapy without delayed toxicity in the 2 weeks preceding the first dose of the combination, were not permitted. Previous systemic treatment in the adjuvant setting was permitted; however, ipilimumab treatment must have ended at least 8 weeks before enrolment. In cohorts including patients who had previously received local therapies, previous treatments could have included, but were not limited to, craniotomy, whole-brain radiotherapy, and stereotactic radiosurgery. Treatment with stereotactic radiosurgery must have occurred at least 14 days before the start of study treatment and whole-brain radiotherapy must have occurred at least 28 days before the start of study treatment. Eligible patients with previous local therapy to all brain lesions must have shown progression of pre-existing target lesions per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 criteria. For cohorts A, B, and C (but not D), patients who were receiving concomitant corticosteroids must have been on a stable or decreasing dose for at least 1 month before study treatment initiation, and no prophylactic or preventative antiepileptic therapy was permitted.

The study protocol was approved by the institutional review board or human research ethics committee at each participating institution ( appendix p 10 ). The study was conducted in accordance with both the Declaration of Helsinki and the International Conference of Harmonisation Good Clinical Practice. All participants provided written informed consent.

Procedures

Patients in each cohort were given oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) until evidence of disease progression, death, or unacceptable toxicity. Dose interruptions or dose reductions down to 75 mg twice per day for dabrafenib and 1 mg once per day for trametinib were permitted to manage adverse events. If a dose reduction of below 75 mg twice daily for dabrafenib and below 1 mg once daily for trametinib was required, the combination study treatment was discontinued. If a dose reduction below 75 mg twice daily for dabrafenib was required, dabrafenib was permanently discontinued, but trametinib could be continued. If a dose reduction below 1 mg once daily for trametinib was required, trametinib was permanently discontinued, but dabrafenib could be continued.

While patients were on study treatment, palliative radiotherapy was permitted for non-target lesions that were either new or present at baseline; however, patients were censored from progression assessment at the time of initiating a new anticancer therapy (either alone or in combination with dabrafenib plus trametinib).

Intracranial disease was assessed by a neuroradiologist, a trained radiologist, or a neurosurgeon at baseline (up to 28 days before the first study dose), week 4, week 8, and every 8 weeks until week 40, using gadolinium contrast-enhanced MRI—the only method accepted for assigning intracranial lesions. After week 40, disease assessments were to be done every 12 weeks. We assessed extracranial disease at the same timepoints using contrast-enhanced CT or MRI. Intracranial disease could be assessed only by contrast-enhanced MRI, and MRI scan slices of 1 mm were required for brain metastases that were 5 mm to less than 10 mm. RECIST was modified to be extended to include up to five intracranial and up to five extracranial target lesions; intracranial target lesions 5–40 mm in diameter were permitted. Confirmation assessments were done no less than 4 weeks after the criteria for response were initially met. If the criteria for a complete or partial response were not confirmed, then stable disease was considered to be the best response if it was observed for a minimum of 8 weeks. An independent assessment of tumour response and progression was done by Bioclinica (Doylestown, PA, USA). Adverse events were graded throughout the study by the investigator per the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0), from the first study dose until 30 days after discontinuation of study treatment. Laboratory assessments evaluating chemistry and haematology parameters, were done at screening, on initiating study treatment (baseline), every 4 weeks through week 36, followed by monthly thereafter, and at the time of study discontinuation. An independent data monitoring committee assessed safety periodically until the primary analysis was done.

Outcomes

The primary endpoint was intracranial response in cohort A, defined as the percentage of patients with a confirmed intracranial complete or partial response assessed by the investigator using modified RECIST version 1.1 criteria. Secondary endpoints were intracranial response in cohorts B, C, and D; intracranial disease control, defined as the percentage of patients with a complete or partial response or stable disease; extracranial response, defined as the percentage of patients with a confirmed extracranial complete or partial response assessed by the investigator using modified RECIST version 1.1 criteria; overall response, defined as the percentage of patients with a confirmed complete or partial response (intracranial or extracranial) by investigator assessment; duration of intracranial, extracranial, and overall response, defined as the time from first documented complete or partial response until the time of disease progression; progression-free survival, defined as the interval between the first dose of study treatment and the earliest date of disease progression or death from any cause; overall survival, defined as the time from first dose until death due to any cause; and safety, measured by the frequency and severity of adverse events per skin, laboratory, vital-sign, cardiac function, and neurological assessment data.

Statistical analysis

This study was designed to assess the null hypothesis of 35% or fewer patients achieving an intracranial response in cohort A and to provide 82% power to detect 50% or more patients in cohort A achieving an intracranial response. Sample sizes were determined to fit the purpose of exploratory analyses and hypothesis generation. We based the sample size of cohort A on the hypothesised improvement in intracranial response. We regarded assessments of intracranial response in other cohorts as exploratory analyses; thus, there were no sample size calculations for cohorts B–D.

We designed the study to have a formal interim analysis for cohort A with a statistical decision rule for futility only, without p-value adjustment. The interim analysis was to take place after 22 patients were treated and had the opportunity for two or more disease assessments. The responses used in this interim analysis did not require confirmation. At least eight of the 22 patients must have had an intracranial response (intracranial complete response or partial response) for the trial to continue. If seven or fewer patients had an intracranial response, this would have been considered as evidence that the null hypothesis was true. Ten of 22 patients had an intracranial response by the time the interim analysis was done (cutoff date Jan 30, 2015); thus, the decision was made to continue the trial. The results presented here are from the primary analysis of activity, which was done when all patients in cohort A had the opportunity for 3 post-baseline disease assessments. The analysis in this Article is regarded as an interim analysis of progression-free survival and overall survival. The final analysis of progression-free survival, overall survival, and safety will occur when 70% of the total enrolled population have died or are lost to follow-up.

We summarised response outcomes using point estimates and two-sided 95% CIs calculated using the unconditional exact method. All analyses were done in the all-treated-patients population (patients who received at least one dose of study drug). We summarised duration of response outcomes, progression-free survival, and overall survival using Kaplan-Meier estimates along with two-sided 95% CIs calculated using the Brookmeyer and Crowley method. Additional endpoint definitions and censoring methods are described in the appendix (p 1) . We summarised adverse events by the number and proportion of total patients, and by system organ class and preferred term, with separate summaries provided for all, drug-related, and serious adverse events and adverse events leading to study treatment discontinuation. The datasets for assessment of all safety endpoints included all safety data collected on patients in the all-treated-patients population. Statistical analyses were done using SAS (version 9.3).

This study is registered with ClinicalTrials.gov , number NCT02039947 .

Role of the funding source

The study was designed by the authors and funder. Data were collected by the study site staff and monitored by the funder, and the funder was involved in the data analysis, data interpretation, and writing of the report. All authors had full access to all data in the study and had final responsibility for the decision to submit for publication.

Results

Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled, of whom 76 were in cohort A, 16 were in cohort B, 16 were in cohort C, and 17 were in cohort D ( figure 1 ). Lactate dehydrogenase concentrations were elevated (higher than the upper limit of normal) in 28 (37%) of 76 patients in cohort A, three (19%) of 16 patients in cohort B, six (38%) of 16 patients in cohort C, and five (29%) of 17 patients in cohort D, and extracranial metastases were present in 68 (89%) of 76 patients in cohort A, 12 (75%) of 16 patients in cohort B, 16 (100%) of 16 patients in cohort C, and 12 (71%) of 17 patients in cohort D ( table 1 ). At the data analysis cutoff, Nov 28, 2016, 14 (18%) of 76 patients in cohort A and two (13%) of 16 patients in cohort B remained on study treatment, whereas all patients in cohorts C and D had discontinued study treatment ( appendix p 2 ). Median follow-up time at the data cutoff (ie, interval between the date of first study treatment dose to the last patient contact date), which varied across cohorts because of differences in timing of enrolment dates for each cohort, was 8·5 months (IQR 5·5–14·0) in cohort A, 20·0 months (8·5–23·5) in cohort B, 9·5 months (4·5–17·5) in cohort C, and 11·0 months (IQR 6·0–20·0) in cohort D. At the data cutoff, eight (50%) of 16 patients in cohort B were still ongoing (on study treatment or in follow-up), which was higher than those ongoing in cohort A (31 [41%] of 76 patients), cohort C (three [19%] of 16 patients), and cohort D (two [12%] of 17 patients; appendix p 2 ).

Figure 1
Trial profile
Data cutoff was on Nov 28, 2016. Cohort A= BRAF V600E -mutant, asymptomatic melanoma brain metastases, without previous local brain-directed therapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Cohort B= BRAF V600E -mutant, asymptomatic melanoma brain metastases, with previous local therapy, ECOG performance status of 0 or 1. Cohort C= BRAF V600D/K/R -mutant, asymptomatic melanoma brain metastases, with or without previous local therapy, ECOG performance status of 0 or 1. Cohort D= BRAF V600D/E/K/R -mutant, symptomatic melanoma brain metastases, with or without previous local therapy ECOG performance status of 0, 1, or 2.
Table 1
Baseline characteristics
Cohort A (n=76) Cohort B (n=16) Cohort C (n=16) Cohort D (n=17)
Age (years)
Median (range) 52·0 (23–84) 54·5 (36–74) 63·0 (44–84) 46·0 (23–68)
<65 60 (79%) 12 (75%) 9 (56%) 16 (94%)
≥65 16 (21%) 4 (25%) 7 (44%) 1 (6%)
Sex
Male 40 (53%) 10 (63%) 11 (69%) 11 (65%)
Female 36 (47%) 6 (38%) 5 (31%) 6 (35%)
ECOG performance status
0 50 (66%) 11 (69%) 12 (75%) 9 (53%)
1 25 (33%) 5 (31%) 4 (25%) 6 (35%)
2 1 (1%) * 0 0 2 (12%)
BRAF genotype
V600E 73 (96%) 16 (100%) 0 15 (88%)
V600K 3 (4%) 0 14 (88%) 1 (6%)
V600R 0 0 2 (13%) 1 (6%)
V600D 0 0 0 0
Target brain metastases
1 41 (54%) 7 (44%) 7 (44%) 7 (41%)
2 20 (26%) 7 (44%) 6 (38%) 7 (41%)
3 7 (9%) 2 (13%) 2 (13%) 1 (6%)
4 4 (5%) 0 0 1 (6%)
5 4 (5%) 0 1 (6%) 1 (6%)
SLD of target intracranial lesions (mm) 20 (6–117) 14 (5–40) 20 (5–61) 33 (10–84)
Extracranial metastases
No 8 (11%) 4 (25%) 0 5 (29%)
Yes 68 (89%) 12 (75%) 16 (100%) 12 (71%)
Lactate dehydrogenase concentration
Normal (≤ULN) 48 (63%) 13 (81%) 10 (63%) 12 (71%)
Elevated (>ULN) 28 (37%) 3 (19%) 6 (38%) 5 (29%)
Receiving steroid therapy
Previous treatment 3 (4%) 1 (6%) 0 5 (29%)
On-treatment or post-treatment 38 (50%) 8 (50%) 9 (56%) 15 (88%)
Previous systemic anticancer treatment
No 59 (78%) 11 (69%) 13 (81%) 10 (59%)
Yes 17 (22%) 5 (31%) 3 (19%) 7 (41%)
Data are median (range) or n (%). Cohort A= BRAF V600E -mutant, asymptomatic melanoma brain metastases, without previous local brain-directed therapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Cohort B= BRAF V600E -mutant, asymptomatic melanoma brain metastases, with previous local therapy, ECOG performance status of 0 or 1. Cohort C= BRAF V600D/K/R -mutant, asymptomatic melanoma brain metastases, with or without previous local therapy, ECOG performance status of 0 or 1. Cohort D= BRAF V600D/E/K/R -mutant, symptomatic melanoma brain metastases, with or without previous local therapy ECOG performance status of 0, 1, or 2. ECOG=Eastern Cooperative Oncology Group. SLD=sum of lesion diameters. ULN=upper limit of normal.

* Patient had ECOG performance status 1 at time of screening and enrolment.

Patients were enrolled on the basis of BRAF V600E status, but were found to be BRAF V600K on central confirmation.

44 (58%; 95% CI 46–69) of 76 patients in cohort A had an investigator-assessed intracranial response, including three (4%) who achieved a complete response and 41 (54%) who achieved a partial response ( table 2 ; figure 2A ). Median duration of investigator-assessed intracranial response was 6·5 months (95% CI 4·9–10·3) in cohort A ( table 2 ; figure 3A ), which was supported by independent review ( appendix p 6 ). Intracranial response was also observed in nine (56%) of 16 patients in cohort B, seven (44%) of 16 patients in cohort C, and ten (59%) of 17 patients in cohort D ( table 2 ; figure 2B–D ). Extracranial responses were observed in 42 (55%; 95% CI 43–67) of 76 patients in cohort A, which lasted a median of 10·2 months (95% CI 5·8 to not estimable), and in seven (44%) of 16 patients in cohort B, 12 (75%) of 16 patients in cohort C, and seven (41%) of 17 patients in cohort D ( table 2 ). Overall responses were achieved by 44 (58%; 95% CI 46–69) of 76 patients in cohort A, which lasted a median of 6·5 months (95% CI 4·9–10·3), and in nine (56%) of 16 patients in cohort B, seven (44%) of 16 patients in cohort C, and 11 (65%) of 17 patients in cohort D ( table 2 ). Disease control in all cohorts, and duration of extracranial, intracranial, and overall responses for cohorts B, C, and D are shown in table 2 . Most of the intracranial, extracranial, and overall responses observed in cohort A occurred by week 4 of study treatment, and by week 4 or week 8 in cohorts B, C, and D ( appendix p 2 ).

Table 2
Investigator-assessed disease response and survival outcomes
Cohort A (n=76) Cohort B (n=16) Cohort C (n=16) Cohort D (n=17)
Intracranial response
Overall intracranial response (CR+PR) 44 (58%; 46–69) 9 (56%; 30–80) 7 (44%; 20–70) 10 (59%; 33–82)
Intracranial disease control (CR+PR+SD) 59 (78%) 14 (88%) 12 (75%) 14 (82%)
Intracranial CR 3 (4%) 1 (6%) 0 1 (6%)
Intracranial PR 41 (54%) 8 (50%) 7 (44%) 9 (53%)
Intracranial SD 15 (20%) 5 (31%) 5 (31%) 4 (24%)
Intracranial PD 14 (18%) 1 (6%) 4 (25%) 3 (18%)
Not evaluable 3 (4%) 1 (6%) 0 0
Intracranial duration of response
Events 29/44 (66%) 6/9 (67%) 4/7 (57%) 8/10 (80%)
Median (95% CI; months) 6·5 (4·9–10·3) 7·3 (3·6–12·6) 8·3 (1·3–15·0) 4·5 (2·8–5·9)
Response at 6 months 63% (45–76) 73% (28–93) 67% (19–90) 13% (1–43)
Extracranial response
Overall extracranial response (CR+PR) 42 (55%; 43–67) 7 (44%; 20–70) 12 (75%; 48–93) 7 (41%; 18–67)
Extracranial disease control (CR+PR+SD) 60 (79%) 11 (69%) 15 (94%) 11 (65%)
Extracranial CR 3 (4%) 1 (6%) 0 0
Extracranial PR 39 (51%) 6 (38%) 12 (75%) 7 (41%)
Extracranial SD 15 (20%) 2 (13%) 2 (13%) 3 (18%)
Extracranial non-CR, non-PD * 3 (4%) 2 (13%) 1 (6%) 1 (6%)
Extracranial PD 6 (8%) 0 0 1 (6%)
Not evaluable 10 (13%) 5 (31%) 1 (6%) 5 (29%)
Extracranial duration of response
Events 16/42 (38%) 0/7 6/12 (50%) 4/7 (57%)
Median (95% CI; months) 10·2 (5·8–NE) NE (NE–NE) 4·9 (3·0–NE) 5·9 (1·8–NE)
Response at 6 months 69% (50–82) 100% (100–100) 40% (10–70) 48% (8–81)
Overall response
Overall response (CR+PR) 44 (58%; 46–69) 9 (56%; 30–80) 7 (44%; 20–70) 11 (65%; 38–86)
Overall disease control (CR+PR+SD) 60 (79%) 14 (88%) 12 (75%) 14 (82%)
Overall CR 1 (1%) 0 0 0
Overall PR 43 (57%) 9 (56%) 7 (44%) 11 (65%)
Overall SD 16 (21%) 5 (31%) 5 (31%) 3 (18%)
Overall PD 14 (18%) 1 (6%) 4 (25%) 3 (18%)
Not evaluable 2 (3%) 1 (6%) 0 0
Overall duration of response
Events 32/44 (73%) 5/9 (56%) 6/7 (86%) 9/11 (82%)
Median (95% CI; months) 6·5 (4·9–10·3) 12·5 (5·3–NE) 6·6 (1·3–16·3) 4·5 (2·8–11·2)
Response at 6 months 57% (41–71) 86% (33–98) 50% (11–80) 23% (3–52)
Progression-free survival (interim)
Events 58 (76%) 10 (63%) 14 (88%) 15 (88%)
Median (95% CI; months) 5·6 (5·3–7·4) 7·2 (4·7–14·6) 4·2 (1·7–6·5) 5·5 (2·8–7·3)
6-month progression-free survival 44% (32–56) 71% (40–88) 31% (10–55) 46% (21–67)
12-month progression-free survival 19% (10–31) 47% (20–71) 16% (3–39) 8% (1–30)
Overall survival (interim)
Events 44 (58%) 7 (44%) 13 (81%) 13 (76%)
Median (95% CI; months) 10·8 (8·7–19·6) 24·3 (7·9–NE) 10·1 (4·6–17·6) 11·5 (6·8–22·4)
6-month overall survival 79% (68–87) 81% (52–94) 69% (40–86) 88% (61–97)
12-month overall survival 46% (33–58) 69% (40–86) 44% (20–66) 44% (20–66)
Data are n (%; 95% CI), n (%), % (95% CI), or n/N (%). Overall response was defined as the percentage of patients with a confirmed overall complete or partial response by assessment using the RECIST 1.1 criteria. To determine the overall response, all target and non-target lesions were assessed using modified RECIST 1.1 criteria. Cohort A= BRAF V600E -mutant, asymptomatic melanoma brain metastases, without previous local brain-directed therapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Cohort B= BRAF V600E -mutant, asymptomatic melanoma brain metastases, with previous local therapy, ECOG performance status of 0 or 1. Cohort C= BRAF V600D/K/R -mutant, asymptomatic melanoma brain metastases, with or without previous local therapy, ECOG performance status of 0 or 1. Cohort D= BRAF V600D/E/K/R -mutant, symptomatic melanoma brain metastases, with or without previous local therapy ECOG performance status of 0, 1, or 2. CR=complete response. PR=partial response. SD=stable disease. PD=progressive disease. NE=not estimable.

* Patients with non-measurable disease at baseline; the response rate relates to the response of the non-target lesion.

No progression event occurred up to the data cutoff date.

Figure 2
Confirmed maxiumum reduction in intracranial target lesion in cohort A (A), cohort B (B), cohort C (C), and cohort D (D)
Grey lines at 20% represent threshold of progression and grey lines at −30% represent threshold of partial response. Cohort A= BRAF V600E -mutant, asymptomatic melanoma brain metastases, without previous local brain-directed therapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Cohort B= BRAF V600E -mutant, asymptomatic melanoma brain metastases, with previous local therapy, ECOG performance status of 0 or 1. Cohort C= BRAF V600D/K/R -mutant, asymptomatic melanoma brain metastases, with or without previous local therapy, ECOG performance status of 0 or 1. Cohort D= BRAF V600D/E/K/R -mutant, symptomatic melanoma brain metastases, with or without previous local therapy ECOG performance status of 0, 1, or 2. Three patients in cohort A were not assessable for intracranial response, one patient in cohort B was not assessable for intracranial response, one patient in cohort C was regarded as not assessable for intracranial response at the first visit and was, therefore, not included in the calculations for this figure, according to the study analysis plan. *Patient had a complete response in the target lesion, but the best confirmed response was determined to be progressive disease due to development of an unequivocal new lesion. †Patient had an unconfirmed complete response, but a best confirmed response was stable disease.
Figure 3
Investigator-assessed duration of intracranial response (A), progression-free survival (B), and preliminary overall survival (C) in cohort A
Crosses denote censored patients.

At the time of analysis, 58 (76%) of 76 patients in cohort A had a progression-free survival event, with an interim median investigator-assessed progression-free survival of 5·6 months (95% CI 5·3–7·4; table 2 , figure 3B ), which was supported by independent review ( appendix p 6 ); 6-month progression-free survival was 44% (95% CI 32–56) and 12-month progression-free survival was 19% (10–31; table 2 ). Median progression-free survival in cohorts B, C, and D is shown in table 2 and the appendix (p 7) . Most patients in all cohorts had progressive disease in intracranial lesions only (66 [53%] of 125 patients) or in both intracranial and extracranial lesions (28 [22%]; appendix p 2 ). The most common type of subsequent systemic therapy received in patients who progressed in all cohorts was immunotherapy, including anti-PD-1 and anti-CTLA-4 regimens ( appendix p 3 ). Some patients also had on-treatment or post-treatment anticancer surgery or radiotherapy ( appendix p 3 ).

At the time of analysis, median time on study treatment across cohorts was 6·0 months (IQR 3·0–11·0), with 24 (19%) of 125 patients treated with dabrafenib plus trametinib for more than 12 months. With treatment or follow-up ongoing for 44 (35%) of 125 patients at the time of analysis, interim median overall survival was 10·8 months (95% CI 8·7–19·6) in cohort A, with 6-month overall survival of 79% (68–87) and 12-month overall survival of 46% (33–58; table 2 , figure 3C , appendix p 8 ). Overall survival results in cohorts B, C, and D are shown in table 2 and the appendix (p 8) .

Adverse events of any grade, regardless of study drug relationship, were observed in 123 (98%) of 125 patients, with 60 (48%) of 125 patients reporting one or more grade 3 or 4 event ( table 3 ), and 44 (35%) of 125 patients reporting serious adverse events ( appendix p 4 ). 108 (86%) of 125 patients had adverse events considered to be related to study treatment ( appendix p 4 ); the most common serious adverse events related to study treatment were pyrexia for dabrafenib (eight [6%] of 125 patients) and decreased ejection fraction (five [4%]) for trametinib ( appendix p 5 ). The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (four [3%] of 125) and headache (three [2%]). Dose interruptions were recorded for 62 (50%) of 125 patients and reductions due to adverse events were recorded for 28 (22%) patients ( appendix p 4 ). Discontinuations due to adverse events occurred in 12 (10%) of 125 patients ( appendix p 4 ), mostly due to decreased ejection fraction (four [3%] of 125 patients; three [4%] of 76 patients in cohort A and one [6%] of 17 patients in cohort D) and pyrexia (three [2%] of 125 patients; one [1%] of 76 patients in cohort A, two [13%] of 16 patients in cohort B). One patient in cohort A had a fatal serious adverse event of intracranial tumour haemorrhage, which was not deemed to be related to study treatment. The primary cause of death in all cases in all cohorts was deemed to be related to cancer, disease progression, or complications due to melanoma.

Table 3
Any-cause adverse events
Cohort A (n=76) Cohort B (n=16) Cohort C (n=16) Cohort D (n=17)
Grade1–2 Grade 3 Grade 4 Grade 5 Grade 1–2 Grade 3 Grade 4 Grade 5 Grade 1–2 Grade 3 Grade 4 Grade 5 Grade 1–2 Grade 3 Grade 4 Grade 5
Any 39 (51%) 30 (39%) 4 (5%) 1 (1%) * 7 (44%) 8 (50%) 1 (6%) 0 7 (44%) 8 (50%) 1 (6%) 0 9 (53%) 7 (41%) 1 (6%) 0
Pyrexia 42 (55%) 2 (3%) 0 0 7 (44%) 0 0 0 7 (44%) 1 (6%) 0 0 7 (41%) 1 (6%) 0 0
Asthenia 27 (36%) 0 0 0 5 (31%) 0 0 0 2 (13%) 1 (6%) 0 0 5 (29%) 0 0 0
Headache 26 (34%) 1 (1%) 0 0 4 (25%) 1 (6%) 0 0 6 (38%) 0 0 0 7 (41%) 1 (6%) 0 0
Nausea 23 (30%) 0 0 0 7 (44%) 0 0 0 4 (25%) 0 0 0 6 (35%) 0 0 0
Diarrhoea 22 (29%) 0 0 0 8 (50%) 0 0 0 3 (19%) 0 0 0 7 (41%) 0 0 0
Vomiting 21 (28%) 1 (1%) 0 0 2 (13%) 0 0 0 2 (13%) 0 0 0 6 (35%) 0 0 0
Chills 16 (21%) 0 0 0 6 (38%) 0 0 0 8 (50%) 0 0 0 5 (29%) 2 (12%) 0 0
Arthralgia 15 (20%) 0 0 0 3 (19%) 0 0 0 2 (13%) 0 0 0 6 (35%) 0 0 0
Myalgia 13 (17%) 0 0 0 5 (31%) 0 0 0 1 (6%) 1 (6%) 0 0 5 (29%) 1 (6%) 0 0
Aspartate aminotransferase increase 11 (14%) 0 0 0 3 (19%) 0 0 0 2 (13%) 0 0 0 3 (18%) 0 0 0
Cough 10 (13%) 0 0 0 2 (13%) 0 0 0 1 (6%) 0 0 0 3 (18%) 0 0 0
Oedema peripheral 10 (13%) 0 0 0 2 (13%) 0 0 0 2 (13%) 0 0 0 3 (18%) 0 0 0
Back pain 9 (12%) 0 0 0 1 (6%) 0 0 0 3 (19%) 0 0 0 2 (12%) 0 0 0
Rash 9 (12%) 0 0 0 6 (38%) 1 (6%) 0 0 3 (19%) 0 0 0 3 (18%) 0 0 0
Constipation 8 (11%) 0 0 0 2 (13%) 0 0 0 4 (25%) 0 0 0 6 (35%) 0 0 0
Decreased appetite 8 (11%) 0 0 0 4 (25%) 0 0 0 7 (44%) 1 (6%) 0 0 3 (18%) 0 0 0
Pain in extremity 8 (11%) 0 0 0 3 (19%) 0 0 0 3 (19%) 0 0 0 2 (12%) 0 0 0
Dizziness 5 (7%) 0 0 0 5 (31%) 0 0 0 0 0 0 0 3 (18%) 0 0 0
Fatigue 7 (9%) 0 0 0 4 (25%) 0 0 0 7 (44%) 1 (6%) 0 0 3 (18%) 0 0 0
Abdominal pain 6 (8%) 0 0 0 2 (13%) 0 0 0 0 0 0 0 5 (29%) 0 0 0
Alanine aminotransferase increased 7 (9%) 0 0 0 2 (13%) 0 0 0 1 (6%) 0 0 0 2 (12%) 1 (6%) 0 0
Dry skin 6 (8%) 0 0 0 2 (13%) 0 0 0 3 (19%) 0 0 0 3 (18%) 0 0 0
Data are n (%). Grade 2 or lower events occurring in 10% or more of patients across cohorts were included. Cohort A= BRAF V600E -mutant, asymptomatic melanoma brain metastases, without previous local brain-directed therapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Cohort B= BRAF V600E -mutant, asymptomatic melanoma brain metastases, with previous local therapy, ECOG performance status of 0 or 1. Cohort C= BRAF V600D/K/R -mutant, asymptomatic melanoma brain metastases, with or without previous local therapy, ECOG performance status of 0 or 1. Cohort D= BRAF V600D/E/K/R -mutant, symptomatic melanoma brain metastases, with or without previous local therapy ECOG performance status of 0, 1, or 2.

* Intracranial tumour haemorrhage, deemed to be unrelated to study treatment.

Discussion

This primary analysis of the COMBI-MB study, representing the first report, to our knowledge, of a phase 2 trial evaluating BRAF and MEK inhibitor combination therapy in patients with BRAF V600E -mutant melanoma brain metastases, provides evidence of activity of dabrafenib plus trametinib in patients with active melanoma brain metastases. The primary endpoint of investigator-assessed intracranial response in cohort A was met. Intracranial responses were also observed in cohorts B, C, and D; however, due to the sample sizes of these cohorts, these findings are considered exploratory and hypothesis generating. Furthermore, dabrafenib and trametinib had a manageable safety profile in this population. The clinical benefits experienced by patients treated with dabrafenib plus trametinib in this study were improved over historic outcomes in patients with melanoma brain metastases treated with local therapies (eg, median overall survival of 3·4 months after whole-brain radiotherapy). 20 However, the durability of clinical responses and disease control were relatively short compared with those in previous trials in patients without melanoma brain metastases. For example, median duration of overall response in this study (eg, 6·5 months in cohort A) was generally shorter than that observed in patients without melanoma brain metastases (eg, 12·0 months in the phase 3 study COMBI-d). 17

The findings of this study suggest that intracranial responses in patients with BRAF V600 -mutant melanoma brain metastases were improved with dabrafenib and trametinib combination therapy compared with previously reported analyses of BRAF inhibitor monotherapy in this setting. Single-agent vemurafenib was associated with intracranial responses in 16% of patients with symptomatic brain metastases and previous CNS-directed therapy, and single-agent dabrafenib has been associated with intracranial responses in 31% of patients with asymptomatic active brain metastases who had previous local therapy and in 39% of patients with asymptomatic active brain metastases who did not previously have therapy. 11 21

In a phase 2 study of ipilimumab in patients with melanoma brain metastases, eight (16%) of 51 asymptomatic patients not requiring steroids and one (5%) of 21 symptomatic patients receiving steroids to control neurological symptoms or perilesional oedema achieved a CNS response, with a median overall survival of 7·0 months for asymptomatic patients and 3·7 months for symptomatic patients. 12 In a phase 2 study of pembrolizumab, which excluded patients receiving steroids to control neurological symptoms or perilesional oedema, four (22%) of 18 patients with untreated or progressive melanoma brain metastases had a brain metastasis response lasting at least 4–10 months. 13 In part 4 of the phase 1 CheckMate 038 study, 22 in patients with active melanoma brain metastases, nivolumab led to an objective response (as defined by RECIST version 1.1) in five (50%) of ten patients both when given alone and when given in combination with ipilimumab, with a median progression-free survival of 10·8 months for the combination (median not reached with nivolumab monotherapy). Notably, patients enrolled in part 4 of CheckMate 038 generally had more favourable baseline clinical features (eg, 20% had elevated lactate dehydrogenase concentration) than those included in our study. The activity of nivolumab plus ipilimumab continues to be evaluated in phase 2 studies, including the anti-PD-1 Brain Collaboration Trial ( NCT02374242 ) and the CheckMate 204 study of the combination in patients with melanoma brain metastases. 23 24

The safety profile of dabrafenib plus trametinib in this study was similar to that reported in previous studies, including in patients with metastatic melanoma without brain metastases, 6 7 14 15 16 17 18 19 in which pyrexia and gastrointestinal issues are common adverse events. 6 7 14 15 16 18 Thus, the combination also has a manageable safety profile in patients with melanoma brain metastases.

Although the initial response and safety data observed in this population are reassuring, the duration of overall response and progression-free survival in all cohorts in this study were shorter than those observed in randomised trials evaluating dabrafenib and trametinib in patients with metastatic melanoma without brain metastases (overall response duration approximately 12–14 months and progression-free survival 11–12 months in phase 3 trials). 6 17 19 Outcomes for patients treated with the combination in this study were similar to those observed in patients with poor clinical features in previous randomised studies evaluating first-line dabrafenib plus trametinib in patients with metastatic melanoma without brain metastases, such as those who had baseline lactate dehydrogenase concentrations of more than double the upper limit of normal (overall response 51%; median progression-free survival 5·5 months). 25 Findings from other studies support the notion that melanoma brain metastases might have distinct molecular features, such as increased activation of the phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) signalling pathway, which has also been associated with resistance to BRAF and MEK inhibitors. 26 27 28 Altogether, these findings support the need for further research in patients with melanoma brain metastases. Additional clinical trials with dabrafenib and trametinib in these patients are also needed, including combinatorial approaches with brain-directed treatments such as stereotactic radiosurgery with or without other systemic therapies.

We acknowledge that the non-randomised one-arm design of COMBI-MB was a limitation for this study, because our results cannot be compared directly with other current treatments. The small sample sizes for cohorts B, C, and D limited the extent of interpretation of results for these patient subsets. Additionally, because of differences in the prevalence of patients with very different eligibility and enrolment numbers required in each cohort, patients in cohorts B, C, and D were enrolled in the study at an earlier date than patients in cohort A, which resulted in differences in median follow-up time between these patient groups. Analyses incorporating information on patients who received surgery or radiosurgery (eg, gamma knife) during or after study treatment might have provided further insights on the appropriate role of dabrafenib plus trametinib in the current treatment landscape of patients with melanoma brain metastases.

Our preliminary results provide evidence that clinical benefit and tolerability is achievable with dabrafenib plus trametinib in a subset of patients with BRAF V600 -mutant metastatic melanoma. Continued follow-up is needed to assess the full effect of dabrafenib plus trametinib on overall survival in these cohorts of patients. Nevertheless, these findings serve as a framework for future studies in this setting, in which effective treatments remain a crucial, unmet medical need.

Contributors

MAD, KTF, and GVL contributed to the study design. MAD, PS, CR, J-JG, KTF, AA, VC-S, LT, TL, LM, SJM, DH, IM-R, MDV, CL, NM, YH, and GVL recruited the patients, collected data, or both. YZ did the statistical analyses. All authors analysed and interpreted the data, drafted the manuscript, and approved the final version.

Declaration of interests

MAD has been a principal investigator with grants to his institution from AstraZeneca, Merck, Roche-Genentech, and Sanofi; and has received personal fees from Novartis, Bristol-Myers Squibb, Sanofi, Roche-Genentech, and Merck for advisory board participation. PS has received personal fees from Amgen, Bristol-Myers Squibb, MSD, Merck-Serono, Pfizer, Roche-Genentech, Pierre Fabre, and Novartis; has received non-financial support from Bristol-Myers Squibb, MSD, Roche-Genentech, and Novartis; and has received a funding grant from Roche-Genentech. CR has received personal fees for advisory board participation from Bristol-Myers Squibb, GlaxoSmithKline, Roche, Merck, Amgen, and Novartis. J-JG has received personal fees for participating in advisory boards for Novartis, Roche, GlaxoSmithKline, Bristol-Myers Squibb, Merck, Amgen, and Pierre Fabre. KTF has received personal fees and grant support from Novartis. AA has received personal fees from Novartis, Roche, MSD, and Bristol-Myers Squibb; and financial support for the study from Novartis. VC-S has participated in advisory boards for MSD, Merck-Serono, Roche, Bristol-Myers Squibb, and Novartis. TL has received grants and personal fees for clinical trials and advisory board participation from Roche, Novartis, and MSD; and received grants and personal fees for clinical trials and honoraria from Bristol-Myers Squibb. LM has been a congress invitation investigator for GlaxoSmithKline. SJM has received personal fees for consultancy or travel from Merck, Amgen, Novartis, and Bristol-Myers Squibb; and has received grants from Merck, Amgen, and Pharmacyclics. DH has received personal fees for advisory board participation, lectures, or both from Roche, Bristol-Myers Squibb, EMD Serono, Merck, Amgen, and Novartis. IM-R has received personal fees from Novartis, Roche, MSD, Amgen, Merck-Serono, Pierre Fabre, Bioncotech, GlaxoSmithKline, and Bristol-Myers Squibb. MDV has consulted or had an advisory role for and received honoraria from Bristol-Myers Squibb, Roche, Novartis, and Merck. CL has received grants from Roche and Bristol-Myers Squibb and personal fees for consultancy, advisory roles, speaker's bureaus, or travel or accommodation expenses from Roche, Bristol-Myers Squibb, Novartis, MSD, Amgen, and GlaxoSmithKline. NM has received personal fees from Roche, Bristol-Myers Squibb, MSD, Novartis, and Amgen; and grants from Bristol-Myers Squibb, MSD, and Pierre Fabre. YZ, YH, and BM are employees of Novartis. GVL received personal fees for her role as a consultant adviser to Amgen, Bristol-Myers Squibb, Merck-MSD, Novartis, Pierre Fabre, Array Biopharma, and Roche. LT declares no competing interests.

Acknowledgments

Medical writing assistance in the form of collating author comments, copy editing, and editorial assistance was provided by Amanda L Kauffman (ArticulateScience, Hamilton, NJ, USA), and funded by Novartis. This study was sponsored by GlaxoSmithKline; dabrafenib and trametinib are assets of Novartis as of March 2, 2015.

Supplementary Material

Supplementary appendix

References

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